This invention generally relates to a method for lowering plasma membrane and cellular cholesterol for the prevention, treatment, cure, or reversal of obesity, metabolic syndrome, diabetes, or a complication relating thereto, by administering to a patient in need thereof, a compound, such as a cyclodextrin or derivative thereof, to lower plasma membrane and cellular cholesterol and/or lipid.
Obesity, metabolic syndrome, pre-diabetes and diabetes represent a worldwide epidemic with a major health care cost, as all these prevalent medical conditions are major risk factors for cardiovascular morbidity and mortality.
It is well established that elevated plasma cholesterol levels and, in particular, low-density lipoprotein (LDL) cholesterol levels, play an important role in the development of coronary heart disease, stroke, peripheral vascular disease, kidney disease, atherosclerosis and hypertension. Clinical trials have demonstrated that decreasing cholesterol concentrations in the plasma has a major impact on cardiovascular morbidity and mortality. Therefore, therapeutic control of systemic hypercholesterolemia is critically important in the clinical management and treatment of obesity, metabolic syndrome, pre-diabetes and diabetes.
While correction of systemic hypercholesterolemia in vascular related disorders has been extensively studied, strategies to reduce local cholesterol accumulation at the plasma membrane and cellular level in target organs of obesity, metabolic syndrome, prediabetes and diabetes have not been studied.
Accumulation of cholesterol in patients with obesity, metabolic syndrome or diabetes has been described in several organs such as pancreas, muscle, liver, blood vessels, kidneys, although the functional consequences of accumulation of local cholesterol in these organs remains to be established.
In both clinical and experimental renal disease, for example, renal accumulation of cholesterol correlates with the development of glomerulosclerosis, and kidneys from diabetic rats are characterized by cholesterol accumulation. Excessive accumulation of cholesterol may be deleterious to cell function though several mechanisms including a modulation of cellular actin cytoskeleton, a modulation of the response of podocytes to several circulating factors (insulin, IGFs, VEGF, any growth factor, apolipoproteins, adipokines, endocrine hormones), a modulation of locally produced inflammatory cytokines, chemokines and their receptors, integrins, a modulation of the immune response (such as the one mediated through TLRs and co-stimulatory molecules as B7-1-CD80), or a modulation of pro- and anti-apoptotic cell death pathways.
Furthermore we have recently demonstrated an important role of a sphingolipid related enzymes (acid sphingomyelinase-like phosphodiesterase 3b, SMPDL3b) as modulators of podocyte function, which are kidney cells heavily affected in diabetes. Similarly, glycosphingolipids accumulate in the kidney of diabetic rats. However, no data are available yet showing a beneficial effect of plasma membrane or cellular cholesterol removal in proteinuric or other renal-related diseases such as diabetic kidney diseases.
Therefore, what is needed is an intervention method that can modulate the accumulation of plasma membrane and cellular cholesterol observed in disease. Such method may then be useful in a preventive and therapeutic strategy for treating, inhibiting or ameliorating such conditions as diabetes, prediabetes, metabolic syndrome, obesity, or symptoms thereof.
Cyclodextrins (CD) are cyclic oligosaccharides that contain 6 or more D-(+) glucopyranose units that are attached by α, β, or γ-(1,4) glucosidic bonds. It has been shown that cyclodextrins are able to form complexes with a variety of hydrophobic molecules due to their unique structure. Cyclodextrin derivatives are extensively used in research labs, for example to remove cholesterol from cultured cells and they are well known in the pharmaceutical industry for their ability to solubilize drugs.
Underivatized cyclodextrins are used throughout the food industry to make cholesterol-free products, such as fat-free butter, eggs and milk products. Hydroxypropyl-beta-cyclodextrin (HPßCD) is recognized as a GRAS (Generally Recognized As Safe) material for use in food products in Asian and European countries and is being considered for similar certification in the United States. Millions of people worldwide are exposed to small amounts of cyclodextrin compounds every day in food, cosmetics and household products. CD derivatives are commercially available from CTD Holdings Inc. (http://cyclodex.com/). Pharmacological studies have suggested that the cholesterol depleting capacities of CD derivatives is approximately 20 times superior to the cholesterol depleting capacities of statins.
In addition to this common exposure to cyclodextrins, the potential safety and efficacy for CD use in therapies has also been recognized. For example, in April 2009, the US Food and Drug Administration (FDA) approved an Investigational New Drug (IND) protocol that allowed twins with a rare brain-destroying cholesterol disease called Niemann Pick disorder to undergo weekly intravenous infusions of HPRCD into their bloodstreams. However, subsequent research discovered that Hydroxypropyl-beta-cyclodextrin does not cross from the bloodstream into the brain. And on Sep. 23, 2010, the FDA granted clearance of an IND application to introduce Trappsol® Cyclo™ (HPßCD) into the brains of six year old identical twin girls dying from Niemann Pick Type C (NPC).
A summary of the IND submission for this indication and route of administration is publicly available at the address (http://addiandcassi.com/wordpress/wp-content/uploads/2009/09/Hydroxy-Propyl-Beta-Cyclodextrin-HPBCD-Summary.pdf).
What has not been previously described are uses of CD and CD derivatives for reducing cellular cholesterol or lipids of obesity, metabolic syndrome, pre-diabetes and diabetes or any related complications.
Advantageously, it has now been discovered that cyclodextrin compounds do not act by affecting the cholesterol synthetic pathway (as do the statins) but primarily by increasing the efflux mechanisms leading to cholesterol accumulation.
This discovery allows for cyclodextrin compounds to be more broadly utilized for the prevention and the cure of obesity, metabolic syndrome, pre-diabetes and diabetes or any related complications. Moreover, cyclodextrin derivatives or any cellular cholesterol-lowering agent belonging to a class of compounds other than statins (such as chromium picolinate, liver X receptor agonists) can also be used in a method as described herein.
One novel strategy to modulate cellular cholesterol include the modulation of sphingolipid related enzymes such as SMPDL3B (sphingomyelin phosphodiesterase, acid-like 3B), which we have demonstrated to modulate cellular cholesterol content and cell function